Primary liver cancer is one of top ten malignant tumors published by the World Health Organization, and its incidence rates in men and in women rank fifth and seventh in the world respectively, ranking third among the deadly diseases caused by cancer. The new and dead cases of each year in the world account for 5.4% of all malignant tumors. In the United States, the incidence rate of primary liver cancer caused by hepatitis C infections has increased year by year. Chronic hepatitis B virus infection, hepatitis C virus infection, alcoholic liver disease, nonalcoholic fatty liver and metabolic related diseases(hemochromatosis) etc., can all lead to the occurrence of liver cancer. About 85% of liver cancer patients develop from progressive liver fibrosis and/or hepatic cirrhosis. Hepatitis B remains the leading cause of cancer in the world. China is a big country with liver diseases. According to statistics, there are more than 100 million people with liver diseases, that is, there is one liver disease patient in every ten people. Among them the most prominent liver disease is the liver cancer which is further evolved from hepatic cirrhosis caused by hepatitis B virus infection. According to the analysis of the global cancer statistics in 2005 from the World Health Organization, currently, the number of new cases of liver cancer in each year is 626,000, and the number of death is 598,000. It is estimated that in the world, 2 billion people suffer from hepatitis B and 200 million people suffer from hepatitis C. Meanwhile, it is also expected that primary liver cancer will become the second cancer-causing deadly disease by 2030. 55% of new patients with liver cancer are from China.
At present, with the development and advancement of medicine, the therapeutic effect of primary liver cancer has been improved to some extent, and the five-year survival rate has reached 40-70%. Comprehensive treatment has become a basic principle of liver cancer treatment, including surgical hepatectomy and liver transplantation, interventional therapy including radiofrequency ablation, microwave therapy and transarterial chemoembolization therapy, etc. Some targeted medicaments have been applied clinically, such as Sorafenib, Sunitinib and so on. However, because of the high invasiveness and high recurrence rate of primary liver cancer, it still seriously affects the therapeutic effect of such patients. Chemotherapy regimens, especially the discovery of new targeting therapeutic drugs, are expected to provide new ways and means for the treatment of liver cancer.
The transient receptor potential (TRP) channel is an important class of cation channel superfamily located on the cell membrane. TRP channels are widely distributed and have different regulatory mechanisms. By sensing various stimuli inside and outside the cell, they participate in many life activities such as algesia, mechanical sensation, genesis of gustatory, maintaining ionic homeostasis in the internal and external environment of cell and so on, having the functions of regulating muscle contraction, transmitter release, cell proliferation, cell differentiation, gene transcription, cell apoptosis and cell death, etc. The TRP channel subtype TRPM8 is a non-selective cation channel which was originally cloned as a prostate-specific protein. At present, TRPM8 has been found to be expressed in pancreatic cancer, colon cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, oral cancer, neuroendocrine tumor, and skin-derived malignant tumor. TRPM8 can be stimulated by cold and activated by menthol. TRPM8 is involved in the regulation of thermesthesia and pain sensation, and can regulate expansion and contraction of blood vessels, especially playing an important role in terms of regulating cell growth and death. Preliminary studies have shown that TRPM8 can play a role by regulating the reproduction and invasion-metastasis ability of tumor cells. Therefore, inhibition of TRPM8 can reduce the incidence of colorectal cancer.
N-(2-aminoethyl)-N-(4-benzyloxy)-3-methoxybenzyl)thiophene-2-formamide hydrochloride (also known as: M8-B hydrochloride, molecular formula: C22H24N2O3S.HCl) has the structural formula I shown below, which can be prepared according to the method of Example 3-1 of International Patent Publication WO2006/040136.

It remains to be further studied that N-(2-aminoethyl)-N-(4-benzyloxy)-3-methoxybenzyl)thiophene-2-formamide hydrochloride causes biological function changes by blocking TRPM8.